Project Summary/Abstract The prevalence of cigarette smoking among people with schizophrenia in the United States is two- to three- times that of the general population. Smokers with schizophrenia have very low rates of smoking cessation, resulting in a disproportionate burden of tobacco-related morbidity and mortality. The overall objective of this project is to develop a novel, theory-driven intervention for smoking cessation for this population. Based on our experimental research, we hypothesize that the primary targets that need to be changed in order to improve cessation outcomes in smokers with schizophrenia are negative affect and smoking urges during abstinence. In smokers without psychiatric illness, varenicline decreases negative affect and smoking urges during abstinence, as well as smoking reward and satisfaction during a smoking lapse. However, the effects of varenicline on these specific target mechanisms in smokers with schizophrenia are unknown. In the R21 phase of this research, we will use an efficient experimental model to conduct a randomized, placebo-controlled investigation of the effects of varenicline on these target mechanisms. If varenicline is found to be effective, we will proceed to an R33 phase, in which we will conduct a randomized, placebo-controlled study to examine whether varenicline, in combination with a novel mobile contingency management (CM) intervention, reduces smoking rates in this population. We will also examine whether the intervention affects smoking through effects on the proposed target mechanisms. This project will provide new and urgently-needed information about factors that contribute to smoking relapse in people with schizophrenia, and information on the feasibility and initial efficacy of a novel intervention for smoking, to indicate whether a larger clinical trial of this intervention is warranted.